LRRK2 phosphorylates novel tau epitopes and promotes tauopathy

Rachel M. Bailey, Jason P. Covy, Heather L. Melrose, Linda Rousseau, Ruth Watkinson, Joshua Knight, Sarah Miles, Matthew J. Farrer, Dennis W. Dickson, Benoit I. Giasson, Jada Lewis

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson's disease (PD). The neuropathology of LRRK2-related PD is heterogeneous and can include aberrant tau phosphorylation or neurofibrillary tau pathology. Recently, LRRK2 has been shown to phosphorylate tau in vitro; however, the major epitopes phosphorylated by LRRK2 and the physiological or pathogenic consequences of these modifications in vivo are unknown. Using mass spectrometry, we identified multiple sites on recombinant tau that are phosphorylated by LRRK2 in vitro, including pT149 and pT153, which are phospho-epitopes that to date have been largely unexplored. Importantly, we demonstrate that expression of transgenic LRRK2 in a mouse model of tauopathy increased the aggregation of insoluble tau and its phosphorylation at T149, T153, T205, and S199/S202/ T205 epitopes. These findings indicate that tau can be a LRRK2 substrate and that this interaction can enhance salient features of human disease.

Original languageEnglish (US)
Pages (from-to)809-827
Number of pages19
JournalActa Neuropathologica
Volume126
Issue number6
DOIs
Publication statusPublished - Dec 1 2013
Externally publishedYes

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Bailey, R. M., Covy, J. P., Melrose, H. L., Rousseau, L., Watkinson, R., Knight, J., ... Lewis, J. (2013). LRRK2 phosphorylates novel tau epitopes and promotes tauopathy. Acta Neuropathologica, 126(6), 809-827. https://doi.org/10.1007/s00401-013-1188-4